Devices, systems and methods for evaluation and feedback of neuromodulation treatment

ABSTRACT

The present disclosure relates to devices, systems and methods for evaluating the success of a treatment applied to tissue in a patient, such as a radio frequency ablative treatment used to neuromodulate nerves associated with the renal artery. A system monitors parameters or values generated during the course of a treatment. Feedback provided to an operator is based on the monitored values and relates to an assessment of the likelihood that a completed treatment was technically successful. In other embodiments, parameters or values generated during the course of an incomplete treatment (such as due to high temperature or high impedance conditions) may be evaluated to provide additional instructions or feedback to an operator.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a continuation of U.S. patent application Ser. No.14/718,843, filed May 21, 2015, now U.S. Pat. No. 9,345,530 which is acontinuation of U.S. patent application Ser. No. 13/281,269, filed Oct.25, 2011, now U.S. Pat. No. 9,066,720, which claims the benefit of thefollowing pending applications:

(a) U.S. Provisional Application No. 61/406,531, filed Oct. 25, 2010;

(b) U.S. Provisional Application No. 61/528,108, filed Aug. 26, 2011;

(c) U.S. Provisional Application No. 61/528,091, filed Aug. 26, 2011;and

(d) U.S. Provisional Application No. 61/528,684, filed Aug. 29, 2011.

All of the foregoing applications are incorporated herein by referencein their entireties. Further, components and features of embodimentsdisclosed in the applications incorporated by reference may be combinedwith various components and features disclosed and claimed in thepresent application.

TECHNICAL FIELD

The present disclosure relates to neuromodulation treatment and, moreparticularly, to devices, systems, and methods for providing evaluationand feedback to an operator of a device providing neuromodulationtreatment.

BACKGROUND

The sympathetic nervous system (SNS) is a primarily involuntary bodilycontrol system typically associated with stress responses. Fibers of theSNS innervate tissue in almost every organ system of the human body andcan affect characteristics such as pupil diameter, gut motility, andurinary output. Such regulation can have adaptive utility in maintaininghomeostasis or in preparing the body for rapid response to environmentalfactors. Chronic activation of the SNS, however, is a common maladaptiveresponse that can drive the progression of many disease states.Excessive activation of the renal SNS in particular has been identifiedexperimentally and in humans as a likely contributor to the complexpathophysiology of hypertension, states of volume overload (such asheart failure), and progressive renal disease. For example, radiotracerdilution has demonstrated increased renal norepinephrine (NE) spilloverrates in patients with essential hypertension.

Cardio-renal sympathetic nerve hyperactivity can be particularlypronounced in patients with heart failure. For example, an exaggeratedNE overflow from the heart and kidneys to plasma is often found in thesepatients. Heightened SNS activation commonly characterizes both chronicand end stage renal disease. In patients with end stage renal disease,NE plasma levels above the median have been demonstrated to bepredictive for cardiovascular diseases and several causes of death. Thisis also true for patients suffering from diabetic or contrastnephropathy. Evidence suggests that sensory afferent signals originatingfrom diseased kidneys are major contributors to initiating andsustaining elevated central sympathetic outflow.

Sympathetic nerves innervating the kidneys terminate in the bloodvessels, the juxtaglomerular apparatus, and the renal tubules.Stimulation of the renal sympathetic nerves can cause increased reninrelease, increased sodium (Na⁺) reabsorption, and a reduction of renalblood flow. These neural regulation components of renal function areconsiderably stimulated in disease states characterized by heightenedsympathetic tone and likely contribute to increased blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome (i.e., renal dysfunction as a progressive complication ofchronic heart failure). Pharmacologic strategies to thwart theconsequences of renal efferent sympathetic stimulation include centrallyacting sympatholytic drugs, beta blockers (intended to reduce reninrelease), angiotensin converting enzyme inhibitors and receptor blockers(intended to block the action of angiotensin II and aldosteroneactivation consequent to renin release), and diuretics (intended tocounter the renal sympathetic mediated sodium and water retention).These pharmacologic strategies, however, have significant limitationsincluding limited efficacy, compliance issues, side effects, and others.Accordingly, there is a strong public-health need for alternativetreatment strategies.

BRIEF DESCRIPTION OF THE DRAWINGS

Many aspects of the present disclosure can be better understood withreference to the following drawings. The components in the drawings arenot necessarily to scale. Instead, emphasis is placed on illustratingclearly the principles of the present disclosure.

FIG. 1 illustrates a renal neuromodulation system configured inaccordance with an embodiment of the present technology.

FIG. 2 illustrates modulating renal nerves with a catheter apparatus inaccordance with an embodiment of the technology.

FIG. 3 is a graph depicting an energy delivery algorithm that may beused in conjunction with the system of FIG. 1 in accordance with anembodiment of the technology.

FIGS. 4 and 5 are block diagrams illustrating algorithms for evaluatinga treatment in accordance with embodiments of the present technology.

FIG. 6 is a block diagram illustrating an algorithm for providingoperator feedback upon occurrence of a high temperature condition inaccordance with an embodiment of the present technology.

FIG. 7 is a block diagram illustrating an algorithm for providingoperator feedback upon occurrence of a high impedance condition inaccordance with an embodiment of the present technology.

FIG. 8 is a block diagram illustrating an algorithm for providingoperator feedback upon occurrence of a high degree of vesselconstriction in accordance with an embodiment of the present technology.

FIG. 9A is a block diagram illustrating an algorithm for providingoperator feedback upon occurrence of an abnormal heart rate condition inaccordance with an embodiment of the present technology.

FIG. 9B is a block diagram illustrating an algorithm for providingoperator feedback upon occurrence of a low blood flow condition inaccordance with an embodiment of the present technology.

FIGS. 10A and 10B are screen shots illustrating representative generatordisplay screens configured in accordance with aspects of the presenttechnology.

FIG. 11 is a conceptual illustration of the sympathetic nervous system(SNS) and how the brain communicates with the body via the SNS.

FIG. 12 is an enlarged anatomic view of nerves innervating a left kidneyto form the renal plexus surrounding the left renal artery.

FIGS. 13A and 13B provide anatomic and conceptual views of a human body,respectively, depicting neural efferent and afferent communicationbetween the brain and kidneys.

FIGS. 14A and 14B are, respectively, anatomic views of the arterial andvenous vasculatures of a human.

DETAILED DESCRIPTION

The present technology is generally directed to devices, systems, andmethods for providing useful evaluation and feedback to a clinician orother practitioner performing a procedure, such as electrically- and/orthermally-induced renal neuromodulation (i.e., rendering neural fibersthat innervate the kidney inert or inactive or otherwise completely orpartially reduced in function). In one embodiment, for example, thefeedback relates to a completed treatment and, in particular, toassessment of the likelihood that the treatment was technicallysuccessful. In some embodiments, one or more parameters (such asparameters related to temperature, impedance, vessel constriction, heartrate, blood flow, and/or patient motion) monitored over the course ofthe treatment may be analyzed based on defined criteria. Based on thisanalysis, an indication may be provided to the operator as to theacceptability or lack of acceptability of the treatment based on thelikelihood of technical success by the treatment.

In other embodiments, feedback and/or instructions may be provided tothe operator regarding a treatment that failed to complete, such as aprocedure that was aborted due to a monitored value associated withtemperature or impedance exceeding a predefined and/or calculatedthreshold or the value being determined to be outside of a predefinedand/or calculated range. In such embodiments, one or more parameters(such as parameters related to temperature, impedance, and/or patientmotion) monitored over the course of the incomplete treatment may beanalyzed based on defined criteria. Based on this analysis, additionalinstructions or feedback may be provided to the operator, such aswhether the treatment site should be imaged to assess whether thetreatment device may have inadvertently moved, or whether additionalattempts at treatment may be performed, and so forth.

Specific details of several embodiments of the technology are describedbelow with reference to FIGS. 1-14B. Although many of the embodimentsare described below with respect to devices, systems, and methods forevaluating neuromodulation treatment, other applications and otherembodiments in addition to those described herein are within the scopeof the technology. Additionally, several other embodiments of thetechnology can have different configurations, components, or proceduresthan those described herein. A person of ordinary skill in the art,therefore, will accordingly understand that the technology can haveother embodiments with additional elements, or the technology can haveother embodiments without several of the features shown and describedbelow with reference to FIGS. 1-14B.

The terms “distal” and “proximal” are used in the following descriptionwith respect to a position or direction relative to the treatingclinician. “Distal” or “distally” are a position distant from or in adirection away from the clinician. “Proximal” and “proximally” are aposition near or in a direction toward the clinician.

I. Renal Neuromodulation

Renal neuromodulation is the partial or complete incapacitation or othereffective disruption of nerves innervating the kidneys. In particular,renal neuromodulation comprises inhibiting, reducing, and/or blockingneural communication along neural fibers (i.e., efferent and/or afferentnerve fibers) innervating the kidneys. Such incapacitation can belong-term (e.g., permanent or for periods of months, years, or decades)or short-term (e.g., for periods of minutes, hours, days, or weeks).Renal neuromodulation is expected to efficaciously treat severalclinical conditions characterized by increased overall sympatheticactivity, and in particular conditions associated with centralsympathetic over stimulation such as hypertension, heart failure, acutemyocardial infarction, metabolic syndrome, insulin resistance, diabetes,left ventricular hypertrophy, chronic and end stage renal disease,inappropriate fluid retention in heart failure, cardio-renal syndrome,and sudden death. The reduction of afferent neural signals contributesto the systemic reduction of sympathetic tone/drive, and renalneuromodulation is expected to be useful in treating several conditionsassociated with systemic sympathetic over activity or hyperactivity.Renal neuromodulation can potentially benefit a variety of organs andbodily structures innervated by sympathetic nerves. For example, areduction in central sympathetic drive may reduce insulin resistancethat afflicts patients with metabolic syndrome and Type II diabetics.Additionally, osteoporosis can be sympathetically activated and mightbenefit from the downregulation of sympathetic drive that accompaniesrenal neuromodulation. A more detailed description of pertinent patientanatomy and physiology is provided in Section IV below.

Various techniques can be used to partially or completely incapacitateneural pathways, such as those innervating the kidney. The purposefulapplication of energy (e.g., electrical energy, thermal energy) totissue by energy delivery element(s) can induce one or more desiredthermal heating effects on localized regions of the renal artery andadjacent regions of the renal plexus RP, which lay intimately within oradjacent to the adventitia of the renal artery. The purposefulapplication of the thermal heating effects can achieve neuromodulationalong all or a portion of the renal plexus RP.

The thermal heating effects can include both thermal ablation andnon-ablative thermal alteration or damage (e.g., via sustained heatingand/or resistive heating). Desired thermal heating effects may includeraising the temperature of target neural fibers above a desiredthreshold to achieve non-ablative thermal alteration, or above a highertemperature to achieve ablative thermal alteration. For example, thetarget temperature can be above body temperature (e.g., approximately37° C.) but less than about 45° C. for non-ablative thermal alteration,or the target temperature can be about 45° C. or higher for the ablativethermal alteration.

More specifically, exposure to thermal energy (heat) in excess of a bodytemperature of about 37° C., but below a temperature of about 45° C.,may induce thermal alteration via moderate heating of the target neuralfibers or of vascular structures that perfuse the target fibers. Incases where vascular structures are affected, the target neural fibersare denied perfusion resulting in necrosis of the neural tissue. Forexample, this may induce non-ablative thermal alteration in the fibersor structures. Exposure to heat above a temperature of about 45° C., orabove about 60° C., may induce thermal alteration via substantialheating of the fibers or structures. For example, such highertemperatures may thermally ablate the target neural fibers or thevascular structures. In some patients, it may be desirable to achievetemperatures that thermally ablate the target neural fibers or thevascular structures, but that are less than about 90° C., or less thanabout 85° C., or less than about 80° C., and/or less than about 75° C.Regardless of the type of heat exposure utilized to induce the thermalneuromodulation, a reduction in renal sympathetic nerve activity(“RSNA”) is expected. A more detailed description of pertinent patientanatomy and physiology is provided in Section IV below.

II. Systems and Methods for Renal Neuromodulation

FIG. 1 illustrates a renal neuromodulation system 10 (“system 10”)configured in accordance with an embodiment of the present technology.The system 10 includes an intravascular treatment device 12 operablycoupled to an energy source or energy generator 26. In the embodimentshown in FIG. 1, the treatment device 12 (e.g., a catheter) includes anelongated shaft 16 having a proximal portion 18, a handle assembly 34 ata proximal region of the proximal portion 18, and a distal portion 20extending distally relative to the proximal portion 18. The treatmentdevice 12 further includes a therapeutic assembly or treatment section22 including an energy delivery element 24 (e.g., an electrode) at ornear the distal portion 20 of the shaft 16. In the illustratedembodiment, a second energy delivery element 24 is illustrated in brokenlines to indicate that the systems and methods disclosed herein can beused with treatment devices having one or more energy delivery elements24. Further, it will be appreciated that although only two energydelivery elements 24 are shown, the treatment device 12 may includeadditional energy delivery elements 24.

The energy generator 26 (e.g., a RF energy generator) is configured togenerate a selected form and magnitude of energy for delivery to thetarget treatment site via the energy delivery element 24. The energygenerator 26 can be electrically coupled to the treatment device 12 viaa cable 28. At least one supply wire (not shown) passes along theelongated shaft 16 or through a lumen in the elongated shaft 16 to theenergy delivery element 24 and transmits the treatment energy to theenergy delivery element 24. A control mechanism, such as foot pedal 32,may be connected (e.g., pneumatically connected or electricallyconnected) to the energy generator 26 to allow the operator to initiate,terminate and, optionally, adjust various operational characteristics ofthe energy generator, including, but not limited to, power delivery. Theenergy generator 26 can be configured to deliver the treatment energyvia an automated control algorithm 30 and/or under the control of aclinician. In addition, one or more evaluation/feedback algorithms 31may be executed on a processor of the system 10. Suchevaluation/feedback algorithms 31, when executed in conjunction with atreatment operation, may provide feedback to a user of the system 10,such as via a display 33 associated with the system 10. The feedback orevaluation may allow an operator of the system 10 to determine thesuccess of a given treatment and/or to evaluate possible failureconditions. This feedback, therefore, may be useful in helping theoperator learn how to increase the likelihood of success when performinga treatment. Further details regarding suitable control algorithms 30and evaluation/feedback algorithms 31 are described below with referenceto FIGS. 3-10B.

In some embodiments, the system 10 may be configured to provide deliveryof a monopolar electric field via the energy delivery element 24. Insuch embodiments, a neutral or dispersive electrode 38 may beelectrically connected to the energy generator 26 and attached to theexterior of the patient (as shown in FIG. 2). Additionally, one or moresensors (not shown), such as one or more temperature (e.g.,thermocouple, thermistor, etc.), impedance, pressure, optical, flow,chemical or other sensors, may be located proximate to or within theenergy delivery element 24 and connected to one or more of the supplywires (not shown). For example, a total of two supply wires may beincluded, in which both wires could transmit the signal from the sensorand one wire could serve dual purpose and also convey the energy to theenergy delivery element 24. Alternatively, both wires could transmitenergy to the energy delivery element 24.

In embodiments including multiple energy delivery element 24, the energydelivery elements 24 may deliver power independently (i.e., may be usedin a monopolar fashion), either simultaneously, selectively, orsequentially, and/or may deliver power between any desired combinationof the elements (i.e., may be used in a bipolar fashion). Furthermore,the clinician optionally may be permitted to choose which energydelivery element(s) 24 are used for power delivery in order to formhighly customized lesion(s) within the renal artery, as desired.

The computing devices on which the system 10 is implemented may includea central processing unit, memory, input devices (e.g., keyboard andpointing devices), output devices (e.g., display devices), and storagedevices (e.g., disk drives). The output devices may be configured tocommunicate with the treatment device 12 (e.g., via the cable 28) tocontrol power to the energy delivery element 24 and/or to obtain signalsfrom the energy delivery element 24 or any associated sensors. Displaydevices may be configured to provide indications of power levels orsensor data, such as audio, visual or other indications, or may beconfigured to communicate the information to another device.

The memory and storage devices are computer-readable media that may beencoded with computer-executable instructions that implement the objectpermission enforcement system, which means a computer-readable mediumthat contains the instructions. In addition, the instructions, datastructures, and message structures may be stored or transmitted via adata transmission medium, such as a signal on a communications link andmay be encrypted. Various communications links may be used, such as theInternet, a local area network, a wide area network, a point-to-pointdial-up connection, a cell phone network, and so on.

Embodiments of the system 10 may be implemented in and used with variousoperating environments that include personal computers, servercomputers, handheld or laptop devices, multiprocessor systems,microprocessor-based systems, programmable consumer electronics, digitalcameras, network PCs, minicomputers, mainframe computers, computingenvironments that include any of the above systems or devices, and soon.

The system 10 may be described in the general context ofcomputer-executable instructions, such as program modules, executed byone or more computers or other devices. Generally, program modulesinclude routines, programs, objects, components, data structures, and soon that perform particular tasks or implement particular abstract datatypes. Typically, the functionality of the program modules may becombined or distributed as desired in various embodiments.

FIG. 2 (and with reference to FIG. 12) illustrates modulating renalnerves with an embodiment of the system 10. The treatment device 12provides access to the renal plexus RP through an intravascular path,such as from a percutaneous access site in the femoral (illustrated),brachial, radial, or axillary artery to a targeted treatment site withina respective renal artery RA. As illustrated, a section of the proximalportion 18 of the shaft 16 is exposed externally of the patient. Bymanipulating the proximal portion 18 of the shaft 16 from outside theintravascular path (e.g., via the handle assembly 34), the clinician mayadvance the shaft 16 through the sometimes tortuous intravascular pathand remotely manipulate or actuate the shaft distal portion 20. Imageguidance, e.g., computed tomography (CT), fluoroscopy, intravascularultrasound (IVUS), optical coherence tomography (OCT), or anothersuitable guidance modality, or combinations thereof, may be used to aidthe clinician's manipulation. Further, in some embodiments, imageguidance components (e.g., IVUS, OCT) may be incorporated into thetreatment device 12 itself. Once proximity between, alignment with, andcontact between the energy delivery element 24 and tissue areestablished within the respective renal artery, the purposefulapplication of energy from the energy generator 26 to tissue by theenergy delivery element 24 induces one or more desired neuromodulatingeffects on localized regions of the renal artery and adjacent regions ofthe renal plexus RP, which lay intimately within, adjacent to, or inclose proximity to the adventitia of the renal artery. The purposefulapplication of the energy may achieve neuromodulation along all or aportion of the renal plexus RP.

The neuromodulating effects are generally a function of, at least inpart, power, time, contact between the energy delivery element(s) 24 andthe vessel wall, and blood flow through the vessel. The neuromodulatingeffects may include denervation, thermal ablation, and non-ablativethermal alteration or damage (e.g., via sustained heating and/orresistive heating). Desired thermal heating effects may include raisingthe temperature of target neural fibers above a desired threshold toachieve non-ablative thermal alteration, or above a higher temperatureto achieve ablative thermal alteration. For example, the targettemperature may be above body temperature (e.g., approximately 37° C.)but less than about 45° C. for non-ablative thermal alteration, or thetarget temperature may be about 45° C. or higher for the ablativethermal alteration. Desired non-thermal neuromodulation effects mayinclude altering the electrical signals transmitted in a nerve.

III. Evaluation of Renal Neuromodulation Treatment

A. Overview

In one implementation, a treatment administered using the system 10constitutes delivering energy through one or more energy deliveryelements (e.g., electrodes) to the inner wall of a renal artery for apredetermined amount of time (e.g., 120 sec). Multiple treatments (e.g.,4-6) may be administered in both the left and right renal arteries toachieve the desired coverage. A technical objective of a treatment maybe, for example, to heat tissue to a depth of at least about 3 mm to atemperature that would lesion a nerve (e.g., about 65° C.). A clinicalobjective of the procedure typically is to neuromodulate (e.g., lesion)a sufficient number of renal nerves (either efferent or afferent nervesof the sympathetic renal plexus) to cause a reduction in sympathetictone. If the technical objective of a treatment is met (e.g., tissue isheated to about 65° C. to a depth of about 3 mm) the probability offorming a lesion of renal nerve tissue is high. The greater the numberof technically successful treatments, the greater the probability ofmodulating a sufficient proportion of renal nerves, and thus the greaterthe probability of clinical success.

Throughout the treatment there may be a number of states that areindicative of a possibility that the treatment may not be successful. Incertain embodiments, based on indications of these states, the operationof the system 10 may be stopped or modified. For example, certainindications may result in cessation of energy delivery and anappropriate message may be displayed, such as on display 33. Factorsthat may result in a display message and/or cessation or modification ofa treatment protocol include, but are not limited to, indications of animpedance, blood flow, and/or temperature measurement or change that isoutside of accepted or expected thresholds and/or ranges that may bepredetermined or calculated. A message can indicate information such asa type of patient condition (e.g., an abnormal patient condition), thetype and/or value of the parameter that falls outside an accepted orexpected threshold, an indication of suggested action for a clinician,or an indication that energy delivery has been stopped. However, if nounexpected or aberrant measurements are observed, energy may continue tobe delivered at the target site in accordance with a programmed profilefor a specified duration resulting in a complete treatment. Following acompleted treatment, energy delivery is stopped and a message indicatingcompletion of the treatment may be displayed.

However, a treatment can be completed without initiating an indicationof an abnormal patient condition and yet an event or combination ofevents could occur that alters (e.g., decreases) the probability of atechnically successful treatment. For example, an electrode that isdelivering energy could move or be inadvertently placed withinsufficient contact between the electrode and the wall of a renalartery, thereby resulting in insufficient lesion depth or temperature.Therefore, even when a treatment is completed without an indication ofabnormal patient condition, it may be difficult to evaluate thetechnical success of the treatment. Likewise, to the extent thatindications of abnormal patient conditions may be reported by the system10, it may be difficult to understand the causes of the abnormal patientconditions (such as temperature and/or impedance values that falloutside of expected ranges).

As noted above, one or more evaluation/feedback algorithms 31 may beprovided that are executed on a processor-based component of the system10, such as one or more components provided with the generator 26. Insuch implementations, the one or more evaluation/feedback algorithms 31may be able to provide a user with meaningful feedback that can be usedin evaluating a given treatment and/or that can be used in learning thesignificance of certain types of abnormal patient conditions and how toreduce the occurrence of such conditions. For example, if a particularparameter (e.g., an impedance or temperature value) causes or indicatesthat treatment did not proceed as expected and (in some instances), mayhave resulted in a technically unsuccessful treatment, the system 10 canprovide feedback (e.g., via the display 33) to alert the clinician. Thealert to the clinician can range from a simple notification ofunsuccessful treatment to a recommendation that a particular parameterof the treatment (e.g., the impedance value(s) during treatment,placement of the energy delivery elements 24 within the patient, etc.)be modified in a subsequent treatment. The system 10 can accordinglylearn from completed treatment cycles and modify subsequent treatmentparameters based on such learning to improve efficacy. Non-exhaustiveexamples of measurements the one or more evaluation/feedback algorithms31 may consider include measurements related to change(s) in temperatureover a specified time, a maximum temperature, a maximum averagetemperature, a minimum temperature, a temperature at a predetermined orcalculated time relative to a predetermined or calculated temperature,an average temperature over a specified time, a maximum blood flow, aminimum blood flow, a blood flow at a predetermined or calculated timerelative to a predetermined or calculated blood flow, an average bloodflow over time, a maximum impedance, a minimum impedance, an impedanceat a predetermined or calculated time relative to a predetermined orcalculated impedance, a change in impedance over a specified time, or achange in impedance relative to a change in temperature over a specifiedtime. Measurements may be taken at one or more predetermined times,ranges of times, calculated times, and/or times when or relative to whena measured event occurs. It will be appreciated that the foregoing listmerely provides a number of examples of different measurements, andother suitable measurements may be used.

B. Control of Applied Energy

With the treatments disclosed herein for delivering therapy to targettissue, it may be beneficial for energy to be delivered to the targetneural structures in a controlled manner. The controlled delivery ofenergy will allow the zone of thermal treatment to extend into the renalfascia while reducing undesirable energy delivery or thermal effects tothe vessel wall. A controlled delivery of energy may also result in amore consistent, predictable and efficient overall treatment.Accordingly, the generator 26 desirably includes a processor including amemory component with instructions for executing an algorithm 30 (seeFIG. 1) for controlling the delivery of power and energy to the energydelivery device. The algorithm 30, a representative embodiment of whichis depicted in FIG. 3, may be implemented as a conventional computerprogram for execution by a processor coupled to the generator 26. Aclinician using step-by-step instructions may also implement thealgorithm 30 manually.

The operating parameters monitored in accordance with the algorithm mayinclude, for example, temperature, time, impedance, power, blood flow,flow velocity, volumetric flow rate, blood pressure, heart rate, etc.Discrete values in temperature may be used to trigger changes in poweror energy delivery. For example, high values in temperature (e.g., 85°C.) could indicate tissue desiccation in which case the algorithm maydecrease or stop the power and energy delivery to prevent undesirablethermal effects to target or non-target tissue. Time additionally oralternatively may be used to prevent undesirable thermal alteration tonon-target tissue. For each treatment, a set time (e.g., 2 minutes) ischecked to prevent indefinite delivery of power.

Impedance may be used to measure tissue changes. Impedance indicates theelectrical property of the treatment site. In thermal inductiveembodiments, when an electric field is applied to the treatment site,the impedance will decrease as the tissue cells become less resistive tocurrent flow. If too much energy is applied, tissue desiccation orcoagulation may occur near the electrode, which would increase theimpedance as the cells lose water retention and/or the electrode surfacearea decreases (e.g., via the accumulation of coagulum). Thus, anincrease in tissue impedance may be indicative or predictive ofundesirable thermal alteration to target or non-target tissue. In otherembodiments, the impedance value may be used to assess contact of theenergy delivery element(s) 24 with the tissue. For multiple electrodeconfigurations (e.g., when the energy delivery element(s) 24 includestwo or more electrodes), a relatively small difference between theimpedance values of the individual electrodes may be indicative of goodcontact with the tissue. For a single electrode configuration, a stablevalue may be indicative of good contact. Accordingly, impedanceinformation from the one or more electrodes may be provided to adownstream monitor, which in turn may provide an indication to aclinician related to the quality of the energy delivery element(s) 24contact with the tissue.

Additionally or alternatively, power is an effective parameter tomonitor in controlling the delivery of therapy. Power is a function ofvoltage and current. The algorithm 30 may tailor the voltage and/orcurrent to achieve a desired power.

Derivatives of the aforementioned parameters (e.g., rates of change)also may be used to trigger changes in power or energy delivery. Forexample, the rate of change in temperature could be monitored such thatpower output is reduced in the event that a sudden rise in temperatureis detected. Likewise, the rate of change of impedance could bemonitored such that power output is reduced in the event that a suddenrise in impedance is detected.

As seen in FIG. 3, when a clinician initiates treatment (e.g., via thefoot pedal 32 illustrated in FIG. 1), the control algorithm 30 includesinstructions to the generator 26 to gradually adjust its power output toa first power level P₁ (e.g., 5 watts) over a first time period t₁(e.g., 15 seconds). The power increase during the first time period isgenerally linear. As a result, the generator 26 increases its poweroutput at a generally constant rate of P₁/t₁. Alternatively, the powerincrease may be non-linear (e.g., exponential or parabolic) with avariable rate of increase. Once P₁ and t₁ are achieved, the algorithmmay hold at P₁ until a new time t₂ for a predetermined period of timet₂−t₁ (e.g., 3 seconds). At t₂ power is increased by a predeterminedincrement (e.g., 1 watt) to P₂ over a predetermined period of time,t₃−t₂ (e.g., 1 second). This power ramp in predetermined increments ofabout 1 watt over predetermined periods of time may continue until amaximum power P_(MAX) is achieved or some other condition is satisfied.In one embodiment, P_(MAX) is 8 watts. In another embodiment P_(MAX) is10 watts. Optionally, the power may be maintained at the maximum powerP_(MAX) for a desired period of time or up to the desired totaltreatment time (e.g., up to about 120 seconds).

In FIG. 3, the algorithm 30 illustratively includes a power-controlalgorithm. However, it should be understood that the algorithm 30alternatively may include a temperature-control algorithm. For example,power may be gradually increased until a desired temperature (ortemperatures) is obtained for a desired duration (or durations). Inanother embodiment, a combination power-control and temperature-controlalgorithm may be provided.

As discussed, the algorithm 30 includes monitoring certain operatingparameters (e.g., temperature, time, impedance, power, flow velocity,volumetric flow rate, blood pressure, heart rate, etc.). The operatingparameters may be monitored continuously or periodically. The algorithm30 checks the monitored parameters against predetermined parameterprofiles to determine whether the parameters individually or incombination fall within the ranges set by the predetermined parameterprofiles. If the monitored parameters fall within the ranges set by thepredetermined parameter profiles, then treatment may continue at thecommanded power output. If monitored parameters fall outside the rangesset by the predetermined parameter profiles, the algorithm 30 adjuststhe commanded power output accordingly. For example, if a targettemperature (e.g., 65° C.) is achieved, then power delivery is keptconstant until the total treatment time (e.g., 120 seconds) has expired.If a first temperature threshold (e.g., 70° C.) is achieved or exceeded,then power is reduced in predetermined increments (e.g., 0.5 watts, 1.0watts, etc.) until a target temperature is achieved. If a second powerthreshold (e.g., 85° C.) is achieved or exceeded, thereby indicating anundesirable condition, then power delivery may be terminated. The systemmay be equipped with various audible and visual alarms to alert theoperator of certain conditions.

The following is a non-exhaustive list of events under which algorithm30 may adjust and/or terminate/discontinue the commanded power output:

(1) The measured temperature exceeds a maximum temperature threshold(e.g., from about 70 to about 85° C.).

(2) The average temperature derived from the measured temperatureexceeds an average temperature threshold (e.g., about 65° C.).

(3) The rate of change of the measured temperature exceeds a rate ofchange threshold.

(4) The temperature rise over a period of time is below a minimumtemperature change threshold while the generator 26 has non-zero output.Poor contact between the energy delivery element(s) 24 and the arterialwall may cause such a condition.

(5) A measured impedance exceeds or falls outside an impedance threshold(e.g., <20 Ohms or >500 Ohms).

(6) A measured impedance exceeds a relative threshold (e.g., impedancedecreases from a starting or baseline value and then rises above thisbaseline value)

(7) A measured power exceeds a power threshold (e.g., >8 Watts or >10Watts).

(8) A measured duration of power delivery exceeds a time threshold(e.g., >120 seconds).

Advantageously, the magnitude of maximum power delivered during renalneuromodulation treatment in accordance with the present technology maybe relatively low (e.g., less than about 15 Watts, less than about 10Watts, less than about 8 Watts, etc.) as compared, for example, to thepower levels utilized in electrophysiology treatments to achieve cardiactissue ablation (e.g., power levels greater than about 15 Watts, greaterthan about 30 Watts, etc.). Since relatively low power levels may beutilized to achieve such renal neuromodulation, the flow rate and/ortotal volume of intravascular infusate injection needed to maintain theenergy delivery element and/or non-target tissue at or below a desiredtemperature during power delivery (e.g., at or below about 50° C., forexample, or at or below about 45° C.) also may be relatively lower thanwould be required at the higher power levels used, for example, inelectrophysiology treatments (e.g., power levels above about 15 Watts).In embodiments in which active cooling is used, the relative reductionin flow rate and/or total volume of intravascular infusate infusionadvantageously may facilitate the use of intravascular infusate inhigher risk patient groups that would be contraindicated were higherpower levels and, thus, correspondingly higher infusate rates/volumesutilized (e.g., patients with heart disease, heart failure, renalinsufficiency and/or diabetes mellitus).

C. Technical Evaluation of a Treatment

FIG. 4 is a block diagram of a treatment algorithm 80 configured inaccordance with an embodiment of the present technology. The algorithm80 is configured to evaluate events in a treatment, determine theprobability of technical success of the treatment and display a messageaccordingly to provide feedback to an operator of the system 10 (oranother suitable treatment system). If the treatment is determined tohave a predetermined probability of sub optimal technical success, amessage indicating that the treatment did not proceed as expected may bedisplayed. Alternative implementations can categorize a treatment intoseveral ranges of probabilities of success, such as probability ofsuccess on a scale of 1 to 5. Similarly, in certain implementations, thealgorithm 80 can evaluate if a treatment belongs in a high probabilityof success category, a very low probability of success category, orsomewhere in between.

Variables that characterize a treatment and that may be used by thealgorithm 80 in evaluating a treatment include, but are not limited to:time (i.e., treatment duration), power, change in temperature, maximumtemperature, mean temperature, blood flow, standard deviation oftemperature or impedance, change in impedance, or combinations of theseor other variables. For example, some or all of the variables may beprovided to the algorithm 80 as treatment data 82. In this generalizeddepiction of an algorithm 80, the treatment data 80 may be assessedbased on a cascade or series of different categories or degrees ofcriteria 84. Favorable assessment of the treatment data 82 in view ofone of the criteria 84 may result in the display (block 86) of a messageindicating the treatment was acceptable or successful. Failure of thetreatment data 82 to be found acceptable in view of a criterion 84 mayresult in the treatment data dropping to the next evaluation criterion84.

In the depicted embodiment, failure of the treatment data to be foundacceptable in view of all of the criteria 84 may result in an additionalevaluation being performed, such as the depicted analysis and scoringstep 88. The output of the analysis and scoring step (e.g., a score 90)may be evaluated (block 92). Based on this evaluation 92, the treatmentmay be deemed acceptable, and the corresponding screen displayed (block86), or not acceptable, and a screen 94 displayed indicating thattreatment did not proceed as expected. In still further embodiments, thealgorithm 80 can include an automatic action (e.g., automatic reductionof the power level supplied to the energy source) in response to anindication that treatment did not proceed as expected.

While FIG. 4 depicts a generalized and simplified implementation of atreatment evaluation algorithm, FIG. 5 depicts a more detailed exampleof one embodiment of a treatment evaluation algorithm 100. The treatmentevaluation algorithm 100 may be computed following the completion of atreatment (block 102), which may be 120 seconds long (as depicted) orsome other suitable duration, and using data and/or measurements derivedover the course of the treatment.

In the depicted embodiment, it is considered likely that the greatestprobability of less than ideal treatment occurs when an electrode is notin consistent contact with the vessel wall. Accordingly, decision blocks104, 106, 108, and 110 in the flowchart are associated with differentcriteria and screen out those treatments that appear to have one or morecriteria outside a pre-determined range (i.e., do not have a highprobability of success) based on observed or measured data 102 over thecourse of the completed treatment. In the depicted embodiment, thosetreatments that are not screened out at decision blocks 104, 106, 108,and 110 enter a linear discriminant analysis (LDA) 112 to furtherevaluate the treatment. In other embodiments, other suitable analysesmay be performed instead of the depicted LDA. Values assigned to eachstep (i.e., evaluation by a respective criterion) and coefficients 114used in the LDA can be derived from data collected from severaltreatments and/or from experience gained from animal studies.

In the depicted embodiment, the first decision block 104 evaluates theinitial temperature response to energy delivery by checking if thechange in average temperature in the first 15 seconds is greater than14° C. In one implementation, average temperature refers to the averageover a short amount of time (e.g., 3 seconds), which essentially filterslarge fluctuations at high frequency caused by pulsatile blood flow. Aswill be appreciated, a temperature rise in the treatment electrode is aresult of heat conducting from tissue to the electrode. If an electrodeis not in sufficient contact with a vessel wall, energy is deliveredinto the blood flowing around it and the temperature of the electrode isnot increased as much. With this in mind, if the change in averagetemperature in the first 15 seconds is greater than, e.g., 14° C., thisinitial temperature response may indicate sufficient electrode contact,contact force, and/or blood flow rate, at least in the beginning of thetreatment and, if no indication that treatment did not proceed asexpected is encountered for the remainder of the treatment, there is nota high probability that the treatment was less than optimal ortechnically unsuccessful. Thus, a positive answer at decision block 104results in a “Treatment Complete” message 120 being displayed. However,if the change in average temperature in the first 15 seconds is lessthan or equal to, e.g., 14° C., this initial temperature response mayindicate that the electrode may not have had sufficient contact with thevessel wall. Thus, a negative answer at decision block 104 results inproceeding to criteria 106 for further evaluation.

At decision block 106 the hottest temperature is evaluated by checkingif the maximum average temperature is greater than, e.g., 56° C. Atemperature rise above a threshold level (e.g., 56° C.), regardless ofduration, may be enough to allow technical success. Thus, a temperatureabove threshold may be sufficient to indicate successful lesionformation despite the fact that at decision block 104 the initial risein temperature did not indicate sufficient contact. For example, theelectrode may not have had sufficient contact initially but then contactcould have been made at least for enough time to cause the vessel wallto heat up such that the temperature sensor in the electrode reads above56° C. A positive result at decision block 106 results in a “TreatmentComplete” message 120 being displayed. However, a negative result atdecision block 106 indicates that the maximum average temperature didnot rise enough. The algorithm 100, therefore, proceeds to decisionblock 108 for further evaluation.

At decision block 108 the mean temperature is evaluated during a periodwhen power is sustained at its maximum amount (i.e., the ramping upperiod is eliminated from the mean calculation). In one embodiment, thisevaluation consists of determining whether the mean real timetemperature is above 53° C. during the period from 45 seconds to 120seconds. In this manner, this criterion checks to determine iftemperature was above a threshold for a certain duration. If decisionblock 108 yields a positive determination then, despite the fact thatthe initial temperature response and the maximum average temperaturewere insufficient to indicate technical success (i.e., decision blocks104 and 106 were failed), the mean temperature during the last 75seconds indicates sufficient contact for sufficient time. For example,it is possible that a sufficient lesion was made and yet the maximumaverage temperature measured in the electrode was not greater than 56°C. because there is high blood flow pulling heat from the electrode.Therefore, a positive result at decision block 108 results in a“Treatment Complete” message 120 being displayed. However, a negativeresult at decision block 108 indicates that the mean real timetemperature in the sustained power stage was not sufficient and thealgorithm 100 proceeds to decision block 110 for further evaluation ofthe treatment.

At decision block 110 the change in impedance is evaluated by checkingif the percentage of impedance change during a predetermined period oftime (e.g., 45 seconds to 114 seconds), is greater than a predeterminedvalue (e.g., 14%) of the initial impedance. The initial impedance isdetermined as the impedance shortly after the beginning of treatment(e.g., at 6 seconds) to eliminate possible misreadings in impedancemeasurement prior to this period (e.g., due to contrast injection). Aswill be appreciated, the impedance of tissue to radiofrequency (RF)electrical current decreases as the tissue temperature increases untilthe tissue is heated enough to cause it to desiccate at which point itsimpedance starts to rise. Therefore, a decrease in tissue impedance canindicate a rise in tissue temperature. The percentage change in realtime impedance over the sustained power stage may be calculated asfollows:

$\begin{matrix}{{\%\mspace{14mu}\Delta\; Z\mspace{14mu}{over}\mspace{14mu}{SS}} = {100*\left( \frac{Z_{6s}^{avg} - \left( {{mean}\mspace{14mu}{RT}\mspace{14mu} Z\mspace{14mu}{over}\mspace{14mu}{SS}} \right)}{Z_{6s}^{avg}} \right)}} & (1)\end{matrix}$If decision block 110 yields a positive determination then, despite thefact that the previous three decision blocks failed to show that therewas a sufficient rise in temperature (i.e., decision blocks 104, 106,and 108 were failed), the change in impedance could indicate that tissuewas heated sufficiently but the temperature sensor in the electrode didnot rise enough. For example, very high blood flow could cause theelectrode temperature to remain relatively low even if the tissue washeated. Therefore, a positive result at decision block 110 results in a“Treatment Complete” message 120 being displayed. However, a negativeresult at decision block 110 results in the algorithm 100 proceeding toperform a LDA 112.

At LDA 112, a combination of events is evaluated along with a rating ofimportance for each event. In the depicted embodiment, for example, thecriteria evaluated at decision blocks 104, 106, 108, 110 are included inthe LDA 112. In addition, in this implementation, three additionalcriteria may be included: (1) standard deviation of average temperature(which can provide an indication of the degree of sliding motion causedby respiration); (2) standard deviation of real time temperature (whichcan provide an indication of variable blood flow and/or contact forceand/or intermittent contact); and (3) adjusted change in averageimpedance at the end of the treatment (which can further characterizechange in impedance and provide an indication of change in temperatureof tissue). If this analysis determines the combination of variables tohave a significant impact on reducing technical success (e.g., a LDAscore <0 at decision block 122) then an “Unexpected Treatment” message124 is displayed. Otherwise, a “Treatment Complete” message 120 isdisplayed.

It will be appreciated that the various parameters described above aremerely representative examples associated with one embodiment of thealgorithm 100, and one or more of these parameters may vary in otherembodiments. Further, the specific values described above with respectto particular portions of the treatment may be modified/changed in otherembodiments based on, for example, different device configurations,electrode configurations, treatment protocols, etc.

As described above, the algorithm 100 is configured to evaluate atreatment and display a message indicating that treatment is completeor, alternatively, that treatment did not proceed as expected. Based onthe message describing the evaluation of the treatment, the clinician(or the system using automated techniques) can then decide whetherfurther treatments may be necessary and/or if one or more parametersshould be modified in subsequent treatments. In the above-describedexamples, for example, the algorithm 100 may evaluate a number ofsituations generally related to poor contact between the electrode andvessel wall to help determine if the treatment was less than optimal.For example, poor contact may occur when an electrode slides back andforth as the patient breaths and the artery moves, when an electrodebecomes displaced when a patient moves, when the catheter is movedinadvertently, when a catheter is not deflected to the degree needed toapply sufficient contact or contact force between the electrode andvessel wall, and/or when an electrode is placed in a precariousposition. Further, as described above, if a particular parameter or setof parameters may have contributed to or resulted in a less than optimaltreatment, the system 10 (FIG. 1) can provide feedback to alert theclinician to modify one or more treatment parameters during a subsequenttreatment. Such evaluation and feedback of a treatment is expected tohelp clinicians learn to improve their placement technique to get bettercontact and reduce the frequency of technically unsuccessful treatments.

D. Feedback Related to High Temperature Conditions

While the preceding describes generalized evaluation of the technicalsuccess of a treatment, another form of feedback that may be useful toan operator of the system 10 (FIG. 1) is feedback related to specifictypes of patient or treatment conditions. For example, the system 10 maygenerate a message related to high temperature conditions. Inparticular, during a treatment while energy is being delivered, tissuetemperature may increase above a specified level. A temperature sensor(e.g., thermocouple, thermistor, etc.) positioned in or near theelectrode provides an indication of temperature in the electrode and, tosome extent, an indication of tissue temperature. The electrode does notheat directly as energy is delivered to tissue. Instead, tissue isheated and the heat conducts to the electrode and the temperature sensorin the electrode. In one implementation, the system 10 may cease energydelivery if the real time temperature rises above a predefined maximumtemperature (e.g., 85° C.). In such an event, the system may generate amessage indicating the high temperature condition. However, depending onthe circumstances, different actions by the clinician may beappropriate.

If tissue becomes too hot, established temperature thresholds can beexceeded. The implications of high tissue temperature are that an acuteconstriction of the artery or a protrusion of the artery wall couldoccur. This can happen right away or within a short time (e.g., about 50seconds to about 100 seconds) after the occurrence of the hightemperature is noted and a message is generated. In such an occurrence,the clinician may be instructed to image the treatment site to watch fora constriction or protrusion before starting another treatment.

FIG. 6, for example, is a block diagram illustrating an algorithm 150for providing operator feedback when a high temperature condition isdetected in accordance with an embodiment of the present technology. Inone implementation the algorithm 150 is executed in response to a hightemperature condition (block 152) and evaluates (decision block 154)data from the treatment to determine if the high temperature conditioninvolved a situation that included sudden instability or if it did not.Sudden instability can be caused, for example, by sudden movement of thepatient or catheter, thereby causing the electrode to be pushed harder(i.e., contact force is increased) into the vessel wall, which couldalso be accompanied by movement to another location. In the event thatsudden instability is not detected at decision block 154, a firstmessage may be displayed (block 156), such as an indication that a hightemperature has been detected and an instruction to image the treatmentsite to determine if the site has been damaged. In the event that suddeninstability is detected at decision block 154, an alternative messagemay be displayed (block 158) that, in addition to indicating theoccurrence of the high temperature and instructing the clinician toimage the treatment site, may also indicate the possibility that theelectrode may have moved from its original site. Such feedback mayprompt the clinician to compare previous images and avoid treating againon either of the original site or the site to which the electrode hasmoved.

E. Feedback Related to High Impedance

As with high temperature, in certain circumstances the system 10(FIG. 1) may generate a message related to the occurrence of highimpedance. As will be appreciated, impedance to RF current passing froma treatment electrode through the body to a dispersive return electrodecan provide an indication of characteristics of the tissue that is incontact with the treatment electrode. For example, an electrodepositioned in the blood stream in a renal artery may measure a lowerimpedance than an electrode contacting the vessel wall. Furthermore, astissue temperature rises its impedance decreases. However, if the tissuegets too hot it may desicate and its impedance may increase. During atreatment as tissue is gradually heated it is expected that impedancewill decrease. A significant rise in impedance can be a result of anundesired situation such as tissue desication or electrode movement. Incertain implementations, the system 10 may be configured to cease energydelivery if the real time impedance rise is higher than a predefinedmaximum change in impedance from the starting impedance.

FIG. 7, for example, is a block diagram illustrating an algorithm 170for providing operator feedback upon occurrence of a high impedancecondition in accordance with an embodiment of the present technology. Inthe depicted embodiment, the algorithm 170 evaluates data from thetreatment and determines if detection of a high impedance event (block172) was likely to involve a situation in which (a) tissue temperaturewas high and desiccation was likely, (b) the electrode moved, or (c)there was poor electrode contact or no electrode contact with the vesselwall. The algorithm 170 evaluates the data to determine which, if any,of these three situations occurred and displays one of three messages174, 176, or 178 accordingly.

In accordance with one embodiment of the algorithm 170, upon detectionof a high impedance (block 172), the maximum average temperature duringthe treatment is evaluated (decision block 180). If this temperature isabove a certain threshold (e.g., at or above 60° C.) then the highimpedance may be attributed to high tissue temperature resulting indesiccation. In this event, message 174 may be displayed instructing theclinician to check for a constriction or protrusion (i.e., to image thetreatment site) and to avoid treating again in the same location.Conversely, if the temperature is below the threshold (e.g., below 60°C.), the algorithm 170 proceeds to decision block 182.

In the depicted embodiment, at decision block 182, the algorithm 170evaluates if the high impedance event occurred early in treatment (e.g.,in the first 20 seconds of energy delivery) when power is relativelylow. If yes, it is unlikely that tissue temperature was high and morelikely that the electrode initially had poor or no contact andsubsequently established better contact, causing impedance to jump. Inthis event message 176 may be displayed instructing the clinician toattempt to establish better contact and repeat treatment at the samesite. However, if the event occurs later in treatment (e.g., more than20 seconds elapsed), the algorithm 170 proceeds to decision block 184.

At decision block 184, the algorithm 170 evaluates when the highimpedance event occurred during treatment. For example, if the eventoccurred after a predetermined period of time (e.g., 45 seconds), whenthe power has reached high levels, the algorithm proceeds to decisionblock 186. However, if the event occurred when power is being ramped upand is not at its highest (e.g., between 20 seconds and 45 seconds), thealgorithm proceeds to decision block 188.

At decision block 186, the algorithm 170 calculates the percentagechange in impedance (% ΔZ) at the time of the high impedance eventcompared to the impedance at a specified time (e.g., 45 seconds). Thisis the period when power is sustained at a high level. In oneembodiment, the percentage change in impedance is calculated as:

$\begin{matrix}{{\%\mspace{14mu}\Delta\; Z} = {100*{\frac{\left\lbrack {\left( {{final}\mspace{14mu}{avg}\mspace{14mu} Z} \right) - \left( {{avg}\mspace{14mu}{Z@45}\mspace{14mu}\sec} \right)} \right\rbrack}{\left( {{avg}\mspace{14mu}{Z@45}\mspace{14mu}\sec} \right)}}}} & (2)\end{matrix}$If % ΔZ is greater than or equal to a predetermined amount (e.g., 7%)then it may be likely that tissue began to desiccate due to hightemperature. In this event, message 174 may be displayed instructing theclinician to check for a constriction or protrusion (i.e., to image thetreatment site) and to avoid treating again in the same location.Otherwise, tissue desiccation is less likely and it is more likely thatthe electrode moved to cause the high impedance event. In this event,message 178 may be displayed notifying the clinician that the electrodemay have moved. In the event the electrode has moved or may have moved,it is unlikely that tissue temperature reached a high level.Accordingly, it is expected that treating in the same location can bedone if there are no or limited other locations to perform anothertreatment.

At decision block 188, the algorithm 170 may determine whether a suddeninstability occurred. If such instability was present, it is likely thatthe electrode moved. In this event, message 178 may be displayednotifying the clinician that the electrode may have moved. As discussedabove, the clinician may exhibit caution and avoid treating the originallocation or the location to which the electrode moved or the clinicianmay opt to treat in the same location if no other sites or a limitednumber of sites are available for further treatment. Otherwise, if nosudden instability occurred, it is more likely that the electrode hadpoor contact. In this event, message 176 may be displayed instructingthe clinician to attempt to establish better contact and that treatingthe same site is safe.

The same objective of detecting high impedance conditions can beachieved using alternate measurements and calculations. For example, ina further embodiment of the algorithm 170, temperature and impedancedata is taken for a sample time interval (e.g., 20 seconds). At ashorter time interval (e.g., every 1.5 seconds), the standard deviationof the impedance and temperature data is calculated. A first standardtemperature for an interval is calculated as the standard deviation ofthe temperature divided by the standard deviation of the temperature atthe initial time interval. If the standard deviation of the impedancemeasurements is greater than or equal to a pre-determined value (e.g.,10 Ohms), and the first standard temperature is greater than apre-determined threshold (e.g., 3), then the algorithm 170 can displaymessage 176, indicating poor electrode contact. However, if the standarddeviation of the impedance measurement is outside the acceptable range,but the first standard temperature is within the acceptable range, thenmessage 178 will be displayed to alert the clinician that there iselectrode instability.

In accordance with a further embodiment of the algorithm 170, theimpedance of two or more electrodes 24 (e.g., positioned on thetreatment region 22 of the catheter 12 of FIG. 1) can each provide anindependent impedance reading. During delivery of the therapeuticassembly 22 to the treatment site (e.g., within the renal artery), theimpedance readings of the electrodes 24 are typically different due tothe anatomy of the vasculature, as the catheter 12 will conform to thepath of least resistance, often bending at vasculature curves to onlycontact one wall of the renal artery. In some embodiments, once thetherapeutic assembly 22 is in position for treatment, the therapeuticassembly 22 can be expanded circumferentially to contact the entirecircumferential surface of a segment of the renal artery wall. Thisexpansion can place multiple electrodes 24 in contact with the renalartery wall. As the therapeutic assembly 22 is expanded into thetreatment configuration and the electrodes 24 make increased contactwith the renal artery wall, the impedance values of the individualelectrodes 24 can increase and/or approach the same value. With good,stable contact, fluctuations of impedance values also reduce asdescribed above. The energy generator 26 can continually or continuouslymonitor the individual impedance values. The values can then be comparedto determine when contact has been effectively made, as an indication ofsuccessful treatment. In further embodiments, a moving average ofimpedance can be compared to a pre-determined range of variability ofimpedance values with limits set to guide stability measures.

F. Feedback Related to Vasoconstriction

In further embodiments, the system 10 may generate a message related tothe occurrence of vasoconstriction. In particular, while treatment isbeing delivered, blood vessels may contract to a less-than-optimaldiameter. Constricted blood vessels can lead to reduced blood flow,increased treatment site temperatures, and increased blood pressure.Vasoconstriction can be measured by sampling the amplitude (the“envelope”) of real-time temperature data. The current envelope can becompared to a previous envelope sample taken (e.g., 200 ms prior). Ifthe difference between the current envelope and the previous time pointenvelope is less than a pre-determined value (e.g., less than −0.5° C.,or, in other words, there is a less than a 0.5 degree reduction in thepresent envelope value compared to the envelope value at the previoustime point), then measurements are taken at a future time point (e.g.,in 5 seconds). If the difference in average temperature at the futuretime point and the current time point is more than a given temperaturethreshold (e.g., more than 1° C.), then an algorithm 800 may determinethat an undesirably high level of constriction exists, and cancease/alter energy delivery. In such an event, the system 10 maygenerate a message indicating the high constriction condition. However,depending on the circumstances, different actions by the clinician maybe appropriate.

FIG. 8, for example, is a block diagram illustrating an algorithm 800for providing operator feedback when a high degree of vesselconstriction is detected in accordance with an embodiment of the presenttechnology. In one implementation, the algorithm 800 is executed inresponse to a high constriction level (e.g., vessels constricted at orbelow a certain diameter) (Block 802) and evaluates (decision block 804)data from the treatment to determine if the high constriction levelinvolved a situation that included sudden instability or if it did not.An indication of sudden instability can indicate that the electrode 24moved.

In the event that sudden instability is not detected at decision block804, a first message may be displayed (block 806), such as an indicationthat a high constriction level has been detected and an instruction to aclinician to reduce treatment power. In further embodiments, the energylevel may be automatically altered in response to the detectedconstriction level. In the event that sudden instability is detected atdecision block 804, an alternative message may be displayed (block 808)that, in addition to indicating the occurrence of the high constrictionlevel and instructions to the clinician, may also indicate thepossibility that the electrode 24 may have moved from its original site.Such feedback may prompt the clinician to alter or cease treatment.

G. Feedback Related to Cardiac Factors

1. Feedback Related to Abnormal Heart Rate

Like other physiological conditions mentioned above, in certaincircumstances the system 10 may generate a message related to theoccurrence of an abnormal heart rate. In particular, while treatment isbeing delivered, heart rate may exceed or fall below desirableconditions (e.g., temporary procedural or chronic bradycardia).Instantaneous heart rate can be determined by measuring real-timetemperature and impedance. More specifically, a real-time temperaturereading can be filtered, for example, between 0.5 Hz and 2.5 Hz using asecond order Butterworth filter. Local maxima of the filtered signal aredetermined. The local maxima are the detected peaks of thereal-temperature signal. The instantaneous beat rate is the intervalbetween the peaks, as the signal peaks correspond to the periodic changein the cardiac cycle.

In one implementation, the system 10 may cease/alter energy delivery ifthe heart rate falls outside a desirable range. In such an event, thesystem may generate a message indicating the adverse heart ratecondition. However, depending on the circumstances, different actions bythe clinician may be appropriate.

FIG. 9A, for example, is a block diagram illustrating an algorithm 900for providing operator feedback/instructions upon detection of anabnormal heart rate condition in accordance with an embodiment of thepresent technology. In one implementation, for example, the algorithm900 may be executed in response to an abnormal heart rate condition(e.g., above or below a pre-determined threshold) (Block 902). Atdecision block 904, the algorithm 900 evaluates data from the treatmentto determine if the detected abnormal heart rate condition involved asituation that included sudden instability. An indication of suddeninstability can indicate that the electrode moved.

In the event that sudden instability is not detected at decision block904, a first message may be displayed to the clinician (block 906), suchas an indication that an abnormal heart rate has been detected and aninstruction to the clinician to reduce treatment power. In furtherembodiments, the energy level may be automatically altered in responseto the detected adverse heart rate. In the event that sudden instabilityis detected at decision block 904, an alternative message may bedisplayed (block 908) that, in addition to indicating the occurrence ofthe abnormal heart rate and instructions to the clinician, may alsoindicate the possibility that the electrode may have moved from itsoriginal site. Such feedback may prompt the clinician to alter or ceasetreatment.

2. Feedback Related to Low Blood Flow

The system 10 may also be configured to generate a message related tolow blood flow conditions. For example, if blood flow falls below acertain level during treatment (or if vessels are undesirably narrow),the convective heat removed from the electrode 24 and tissue surface isreduced. Excessively high tissue temperatures can lead to the negativeoutcomes described above, such as thrombosis, charring, unreliablelesion size, etc. Reducing power from the generator 26 to prevent thetissue from reaching an unacceptable temperature can lead toinsufficient lesion depth, and nerves may not be heated to sufficientablation temperatures. An algorithm can be used to measure blood flow orthe loss of heat to the blood stream. In one embodiment, blood flow canbe measured with a flow meter or a Doppler sensor placed in the renalartery on a separate catheter or on the treatment catheter 12. Inanother embodiment, heat loss or thermal decay can be measured bydelivering energy (e.g., RF energy) to raise a blood, tissue, orsubstrate temperature. The energy can be turned off and the algorithmcan include monitoring the temperature as a gauge of thermal decay. Arapid thermal decay may represent sufficient blood flow, while a gradualthermal decay may represent low blood flow. For example, in oneembodiment, the algorithm 910 can indicate a low blood flow if the slopeof real-time temperature measurements over the starting temperatureexceeds a preset threshold (e.g., 2.75) and the average temperature isgreater than a preset temperature (e.g., 65° C.). In furtherembodiments, thermal decay and/or blood flow can be characterized bymeasuring temperature oscillations of an electrode delivering RF orresistive heat. At a given temperature or power deliveryamplitude/magnitude, a narrow oscillation range may indicate arelatively low thermal decay/blood flow.

FIG. 9B, for example, is a block diagram illustrating an algorithm 910for providing operator feedback/instructions upon occurrence of a lowblood flow condition in accordance with an embodiment of the presenttechnology. In one implementation, the algorithm 910 is executed inresponse to a detected low blood flow condition (e.g., flow below apre-determined threshold) (Block 912). At block 914, the algorithm 910evaluates data from the treatment to determine if the low blood flowcondition involved a situation that included sudden instability. In theevent that sudden instability is not detected at decision block 914, afirst message may be displayed (block 916), such as an indication thatlow blood flow has been detected and an instruction to a clinician toreduce treatment power. In the event that sudden instability isdetected, an alternative message may be displayed (block 918) that, inaddition to indicating the occurrence of low blood flow and instructionsto the clinician, may also indicate the possibility that the electrodemay have moved from its original site. As noted above, such feedback mayprompt the clinician to alter or cease treatment.

In further embodiments, if blood flow or thermal decay values are lowerthan a typical or pre-determined threshold, the energy deliveryalgorithm 910 can include automatically altering one or more conditionsor characteristics of treatment or of the catheter to improve bloodflow. For example, in one embodiment, the algorithm 910 can respond to alow blood flow by pulsing the energy provided to the energy deliveryelement 24 rather than providing continuous energy. This may allow thelower blood flow to more adequately remove heat from the tissue surfacewhile still creating a sufficiently deep lesion to ablate a nerve.

In another embodiment, the algorithm 910 can include responding to a lowblood flow by cooling the electrodes, as described in further detail inInternational Patent Application No. PCT/US2011/033491, filed Apr. 26,2011, and U.S. patent application Ser. No. 12/874,457, filed Aug. 30,2010. The foregoing applications are incorporated herein by reference intheir entireties.

In a further embodiment, the algorithm 910 can respond to a low bloodflow by requiring a manual increase of blood flow to the region. Forexample, a non-occlusive balloon can be inflated in the abdominal aorta,thereby increasing pressure and flow in the renal artery. The ballooncan be incorporated on the treatment catheter or on a separate catheter.

H. Feedback Display

FIGS. 10A and 10B are screen shots illustrating representative generatordisplay screens configured in accordance with aspects of the presenttechnology. FIG. 10A, for example, is a display screen 1100 for enhancedimpedance tracking during treatment. The display 1100 includes agraphical display 1110 that tracks impedance measurements in real timeover a selected period of time (e.g., 100 seconds). This graphicaldisplay 1110, for example, can be a dynamic, rolling display that isupdated at periodic intervals to provide an operator with bothinstantaneous and historical tracking of impedance measurements. Thedisplay 1110 can also includes an impedance display 1120 with thecurrent impedance as well as a standard deviation indication 1122 forthe impedance. In one embodiment, the standard deviation indication 1122is configured to flash when this value is greater than 10. Such anindication can alert the operator of a contrast injection that isaffecting the measurement or that the electrode may be unstable. Furtherinformation about contrast injection indications are described below.

FIG. 10B, for example, is another representative display screen 1130with additional information for an operator. In this example, thedisplay screen 1130 is configured to alert the operator of a contrastinjection and that the system is waiting for contrast to clear beforecommencing (e.g., disable RF for approximately 1 to 2 seconds untilcontrast clears). In another embodiment, the display screen 1130 may beconfigured to provide other alert messages (e.g., “POSSIBLE UNSTABLEELECTRODE,” etc.). The additional information provided in the displayscreens 1110 and 1130 described above is expected to improve contactassessment prior to RF ON, and improve treatment efficiency andefficacy.

The additional information described above with reference to FIGS. 10Aand 10B can be generated based on the algorithms described herein, orother suitable algorithms. In one embodiment, for example, an algorithmcan continuously check for contrast injection/stability during pre-RFON. If the electrode is stable and there is no contrast for ≧1 second,the baseline impedance Z is set equal to the average impedance Z over 1second. In one particular example, the real time impedance is comparedwith two standard deviations of the mean impedance value within a onesecond window. In another specific example, the real time impedance maybe compared with a fixed number (e.g., determine if the standarddeviation is greater than 10). In still other examples, otherarrangements may be used.

If the real time impedance measurement is within this range, no messageis displayed. However, if the real time impedance is not within twostandard deviations of the mean, the electrode may not stable (i.e.,drifting, moving, etc.) and one or both of the message(s) describedabove with reference to FIGS. 10A and 10B may be displayed to the user(e.g., “WAITING FOR CONTRAST TO CLEAR,” “POSSIBLE UNSTABLE ELECTRODE”).By way of example, for contrast injection detection, in addition to thestandard deviation of the impedance, the algorithm may be configured tofactor in the standard deviation of a real time temperature measurementto look for excursions of the real time temperature below a startingbody temperature. The exact value for the temperature excursion cut offcan vary. In one particular example, the system is configured such thatif there is an increase in impedance (e.g., standard deviation >10)accompanied by a drop in real time temperature, the system will flag aContrast Detected event leading to the “WAITING FOR CONTRAST TO CLEAR”message to be displayed to the operator. In other examples, however,other algorithms and/or ranges may be used to determine contrastinjection events and/or the stability of the electrode. Further, in someembodiments the system may modify/adjust various treatment parametersbased on detected conditions without displaying such messages to theclinician.

IV. Pertinent Anatomy and Physiology

The following discussion provides further details regarding pertinentpatient anatomy and physiology. This section is intended to supplementand expand upon the previous discussion regarding the relevant anatomyand physiology, and to provide additional context regarding thedisclosed technology and the therapeutic benefits associated with renaldenervation. For example, as mentioned previously, several properties ofthe renal vasculature may inform the design of treatment devices andassociated methods for achieving renal neuromodulation via intravascularaccess, and impose specific design requirements for such devices.Specific design requirements may include accessing the renal artery,facilitating stable contact between the energy delivery elements of suchdevices and a luminal surface or wall of the renal artery, and/oreffectively modulating the renal nerves with the neuromodulatoryapparatus.

A. The Sympathetic Nervous System

The Sympathetic Nervous System (SNS) is a branch of the autonomicnervous system along with the enteric nervous system and parasympatheticnervous system. It is always active at a basal level (called sympathetictone) and becomes more active during times of stress. Like other partsof the nervous system, the sympathetic nervous system operates through aseries of interconnected neurons. Sympathetic neurons are frequentlyconsidered part of the peripheral nervous system (PNS), although manylie within the central nervous system (CNS). Sympathetic neurons of thespinal cord (which is part of the CNS) communicate with peripheralsympathetic neurons via a series of sympathetic ganglia. Within theganglia, spinal cord sympathetic neurons join peripheral sympatheticneurons through synapses. Spinal cord sympathetic neurons are thereforecalled presynaptic (or preganglionic) neurons, while peripheralsympathetic neurons are called postsynaptic (or postganglionic) neurons.

At synapses within the sympathetic ganglia, preganglionic sympatheticneurons release acetylcholine, a chemical messenger that binds andactivates nicotinic acetylcholine receptors on postganglionic neurons.In response to this stimulus, postganglionic neurons principally releasenoradrenaline (norepinephrine). Prolonged activation may elicit therelease of adrenaline from the adrenal medulla.

Once released, norepinephrine and epinephrine bind adrenergic receptorson peripheral tissues. Binding to adrenergic receptors causes a neuronaland hormonal response. The physiologic manifestations include pupildilation, increased heart rate, occasional vomiting, and increased bloodpressure. Increased sweating is also seen due to binding of cholinergicreceptors of the sweat glands.

The sympathetic nervous system is responsible for up- anddown-regulating many homeostatic mechanisms in living organisms. Fibersfrom the SNS innervate tissues in almost every organ system, providingat least some regulatory function to things as diverse as pupildiameter, gut motility, and urinary output. This response is also knownas sympatho-adrenal response of the body, as the preganglionicsympathetic fibers that end in the adrenal medulla (but also all othersympathetic fibers) secrete acetylcholine, which activates the secretionof adrenaline (epinephrine) and to a lesser extent noradrenaline(norepinephrine). Therefore, this response that acts primarily on thecardiovascular system is mediated directly via impulses transmittedthrough the sympathetic nervous system and indirectly via catecholaminessecreted from the adrenal medulla.

Science typically looks at the SNS as an automatic regulation system,that is, one that operates without the intervention of consciousthought. Some evolutionary theorists suggest that the sympatheticnervous system operated in early organisms to maintain survival as thesympathetic nervous system is responsible for priming the body foraction. One example of this priming is in the moments before waking, inwhich sympathetic outflow spontaneously increases in preparation foraction.

1. The Sympathetic Chain

As shown in FIG. 11, the SNS provides a network of nerves that allowsthe brain to communicate with the body. Sympathetic nerves originateinside the vertebral column, toward the middle of the spinal cord in theintermediolateral cell column (or lateral horn), beginning at the firstthoracic segment of the spinal cord and are thought to extend to thesecond or third lumbar segments. Because its cells begin in the thoracicand lumbar regions of the spinal cord, the SNS is said to have athoracolumbar outflow. Axons of these nerves leave the spinal cordthrough the anterior rootlet/root. They pass near the spinal (sensory)ganglion, where they enter the anterior rami of the spinal nerves.However, unlike somatic innervation, they quickly separate out throughwhite rami connectors which connect to either the paravertebral (whichlie near the vertebral column) or prevertebral (which lie near theaortic bifurcation) ganglia extending alongside the spinal column.

In order to reach the target organs and glands, the axons should travellong distances in the body, and, to accomplish this, many axons relaytheir message to a second cell through synaptic transmission. The endsof the axons link across a space, the synapse, to the dendrites of thesecond cell. The first cell (the presynaptic cell) sends aneurotransmitter across the synaptic cleft where it activates the secondcell (the postsynaptic cell). The message is then carried to the finaldestination.

In the SNS and other components of the peripheral nervous system, thesesynapses are made at sites called ganglia. The cell that sends its fiberis called a preganglionic cell, while the cell whose fiber leaves theganglion is called a postganglionic cell. As mentioned previously, thepreganglionic cells of the SNS are located between the first thoracic(T1) segment and third lumbar (L3) segments of the spinal cord.Postganglionic cells have their cell bodies in the ganglia and sendtheir axons to target organs or glands.

The ganglia include not just the sympathetic trunks but also thecervical ganglia (superior, middle and inferior), which sendssympathetic nerve fibers to the head and thorax organs, and the celiacand mesenteric ganglia (which send sympathetic fibers to the gut).

2. Innervation of the Kidneys

As FIG. 12 shows, the kidney is innervated by the renal plexus RP, whichis intimately associated with the renal artery. The renal plexus RP isan autonomic plexus that surrounds the renal artery and is embeddedwithin the adventitia of the renal artery. The renal plexus RP extendsalong the renal artery until it arrives at the substance of the kidney.Fibers contributing to the renal plexus RP arise from the celiacganglion, the superior mesenteric ganglion, the aorticorenal ganglionand the aortic plexus. The renal plexus RP, also referred to as therenal nerve, is predominantly comprised of sympathetic components. Thereis no (or at least very minimal) parasympathetic innervation of thekidney.

Preganglionic neuronal cell bodies are located in the intermediolateralcell column of the spinal cord. Preganglionic axons pass through theparavertebral ganglia (they do not synapse) to become the lessersplanchnic nerve, the least splanchnic nerve, first lumbar splanchnicnerve, second lumbar splanchnic nerve, and travel to the celiacganglion, the superior mesenteric ganglion, and the aorticorenalganglion. Postganglionic neuronal cell bodies exit the celiac ganglion,the superior mesenteric ganglion, and the aorticorenal ganglion to therenal plexus RP and are distributed to the renal vasculature.

3. Renal Sympathetic Neural Activity

Messages travel through the SNS in a bidirectional flow. Efferentmessages may trigger changes in different parts of the bodysimultaneously. For example, the sympathetic nervous system mayaccelerate heart rate; widen bronchial passages; decrease motility(movement) of the large intestine; constrict blood vessels; increaseperistalsis in the esophagus; cause pupil dilation, piloerection (goosebumps) and perspiration (sweating); and raise blood pressure. Afferentmessages carry signals from various organs and sensory receptors in thebody to other organs and, particularly, the brain.

Hypertension, heart failure and chronic kidney disease are a few of manydisease states that result from chronic activation of the SNS,especially the renal sympathetic nervous system. Chronic activation ofthe SNS is a maladaptive response that drives the progression of thesedisease states. Pharmaceutical management of therenin-angiotensin-aldosterone system (RAAS) has been a longstanding, butsomewhat ineffective, approach for reducing over-activity of the SNS.

As mentioned above, the renal sympathetic nervous system has beenidentified as a major contributor to the complex pathophysiology ofhypertension, states of volume overload (such as heart failure), andprogressive renal disease, both experimentally and in humans. Studiesemploying radiotracer dilution methodology to measure overflow ofnorepinephrine from the kidneys to plasma revealed increased renalnorepinephrine (NE) spillover rates in patients with essentialhypertension, particularly so in young hypertensive subjects, which inconcert with increased NE spillover from the heart, is consistent withthe hemodynamic profile typically seen in early hypertension andcharacterized by an increased heart rate, cardiac output, andrenovascular resistance. It is now known that essential hypertension iscommonly neurogenic, often accompanied by pronounced sympathetic nervoussystem overactivity.

Activation of cardiorenal sympathetic nerve activity is even morepronounced in heart failure, as demonstrated by an exaggerated increaseof NE overflow from the heart and the kidneys to plasma in this patientgroup. In line with this notion is the recent demonstration of a strongnegative predictive value of renal sympathetic activation on all-causemortality and heart transplantation in patients with congestive heartfailure, which is independent of overall sympathetic activity,glomerular filtration rate, and left ventricular ejection fraction.These findings support the notion that treatment regimens that aredesigned to reduce renal sympathetic stimulation have the potential toimprove survival in patients with heart failure.

Both chronic and end stage renal disease are characterized by heightenedsympathetic nervous activation. In patients with end stage renaldisease, plasma levels of norepinephrine above the median have beendemonstrated to be predictive for both all-cause death and death fromcardiovascular disease. This is also true for patients suffering fromdiabetic or contrast nephropathy. There is compelling evidencesuggesting that sensory afferent signals originating from the diseasedkidneys are major contributors to initiating and sustaining elevatedcentral sympathetic outflow in this patient group; this facilitates theoccurrence of the well known adverse consequences of chronic sympatheticover activity, such as hypertension, left ventricular hypertrophy,ventricular arrhythmias, sudden cardiac death, insulin resistance,diabetes, and metabolic syndrome.

(i) Renal Sympathetic Efferent Activity

Sympathetic nerves to the kidneys terminate in the blood vessels, thejuxtaglomerular apparatus and the renal tubules. Stimulation of therenal sympathetic nerves causes increased renin release, increasedsodium (Na+) reabsorption, and a reduction of renal blood flow. Thesecomponents of the neural regulation of renal function are considerablystimulated in disease states characterized by heightened sympathetictone and clearly contribute to the rise in blood pressure inhypertensive patients. The reduction of renal blood flow and glomerularfiltration rate as a result of renal sympathetic efferent stimulation islikely a cornerstone of the loss of renal function in cardio-renalsyndrome, which is renal dysfunction as a progressive complication ofchronic heart failure, with a clinical course that typically fluctuateswith the patient's clinical status and treatment. Pharmacologicstrategies to thwart the consequences of renal efferent sympatheticstimulation include centrally acting sympatholytic drugs, beta blockers(intended to reduce renin release), angiotensin converting enzymeinhibitors and receptor blockers (intended to block the action ofangiotensin II and aldosterone activation consequent to renin release)and diuretics (intended to counter the renal sympathetic mediated sodiumand water retention). However, the current pharmacologic strategies havesignificant limitations including limited efficacy, compliance issues,side effects and others.

(ii) Renal Sensory Afferent Nerve Activity

The kidneys communicate with integral structures in the central nervoussystem via renal sensory afferent nerves. Several forms of “renalinjury” may induce activation of sensory afferent signals. For example,renal ischemia, reduction in stroke volume or renal blood flow, or anabundance of adenosine enzyme may trigger activation of afferent neuralcommunication. As shown in FIGS. 13A and 13B, this afferentcommunication might be from the kidney to the brain or might be from onekidney to the other kidney (via the central nervous system). Theseafferent signals are centrally integrated and may result in increasedsympathetic outflow. This sympathetic drive is directed towards thekidneys, thereby activating the RAAS and inducing increased reninsecretion, sodium retention, volume retention and vasoconstriction.Central sympathetic over activity also impacts other organs and bodilystructures innervated by sympathetic nerves such as the heart and theperipheral vasculature, resulting in the described adverse effects ofsympathetic activation, several aspects of which also contribute to therise in blood pressure.

The physiology therefore suggests that (i) modulation of tissue withefferent sympathetic nerves will reduce inappropriate renin release,salt retention, and reduction of renal blood flow, and that (ii)modulation of tissue with afferent sensory nerves will reduce thesystemic contribution to hypertension and other disease statesassociated with increased central sympathetic tone through its directeffect on the posterior hypothalamus as well as the contralateralkidney. In addition to the central hypotensive effects of afferent renaldenervation, a desirable reduction of central sympathetic outflow tovarious other sympathetically innervated organs such as the heart andthe vasculature is anticipated.

B. Additional Clinical Benefits of Renal Denervation

As provided above, renal denervation is likely to be valuable in thetreatment of several clinical conditions characterized by increasedoverall and particularly renal sympathetic activity such ashypertension, metabolic syndrome, insulin resistance, diabetes, leftventricular hypertrophy, chronic end stage renal disease, inappropriatefluid retention in heart failure, cardio-renal syndrome, and suddendeath. Since the reduction of afferent neural signals contributes to thesystemic reduction of sympathetic tone/drive, renal denervation mightalso be useful in treating other conditions associated with systemicsympathetic hyperactivity. Accordingly, renal denervation may alsobenefit other organs and bodily structures innervated by sympatheticnerves, including those identified in FIG. 11. For example, aspreviously discussed, a reduction in central sympathetic drive mayreduce the insulin resistance that afflicts people with metabolicsyndrome and Type II diabetics. Additionally, patients with osteoporosisare also sympathetically activated and might also benefit from the downregulation of sympathetic drive that accompanies renal denervation.

C. Achieving Intravascular Access to the Renal Artery

In accordance with the present technology, neuromodulation of a leftand/or right renal plexus RP, which is intimately associated with a leftand/or right renal artery, may be achieved through intravascular access.As FIG. 14A shows, blood moved by contractions of the heart is conveyedfrom the left ventricle of the heart by the aorta. The aorta descendsthrough the thorax and branches into the left and right renal arteries.Below the renal arteries, the aorta bifurcates at the left and rightiliac arteries. The left and right iliac arteries descend, respectively,through the left and right legs and join the left and right femoralarteries.

As FIG. 14B shows, the blood collects in veins and returns to the heart,through the femoral veins into the iliac veins and into the inferiorvena cava. The inferior vena cava branches into the left and right renalveins. Above the renal veins, the inferior vena cava ascends to conveyblood into the right atrium of the heart. From the right atrium, theblood is pumped through the right ventricle into the lungs, where it isoxygenated. From the lungs, the oxygenated blood is conveyed into theleft atrium. From the left atrium, the oxygenated blood is conveyed bythe left ventricle back to the aorta.

As will be described in greater detail later, the femoral artery may beaccessed and cannulated at the base of the femoral triangle justinferior to the midpoint of the inguinal ligament. A catheter may beinserted percutaneously into the femoral artery through this accesssite, passed through the iliac artery and aorta, and placed into eitherthe left or right renal artery. This comprises an intravascular paththat offers minimally invasive access to a respective renal arteryand/or other renal blood vessels.

The wrist, upper arm, and shoulder region provide other locations forintroduction of catheters into the arterial system. For example,catheterization of either the radial, brachial, or axillary artery maybe utilized in select cases. Catheters introduced via these accesspoints may be passed through the subclavian artery on the left side (orvia the subclavian and brachiocephalic arteries on the right side),through the aortic arch, down the descending aorta and into the renalarteries using standard angiographic technique.

D. Properties and Characteristics of the Renal Vasculature

Since neuromodulation of a left and/or right renal plexus RP may beachieved in accordance with the present technology through intravascularaccess, properties and characteristics of the renal vasculature mayimpose constraints upon and/or inform the design of apparatus, systems,and methods for achieving such renal neuromodulation. Some of theseproperties and characteristics may vary across the patient populationand/or within a specific patient across time, as well as in response todisease states, such as hypertension, chronic kidney disease, vasculardisease, end-stage renal disease, insulin resistance, diabetes,metabolic syndrome, etc. These properties and characteristics, asexplained herein, may have bearing on the efficacy of the procedure andthe specific design of the intravascular device. Properties of interestmay include, for example, material/mechanical, spatial, fluiddynamic/hemodynamic and/or thermodynamic properties.

As discussed previously, a catheter may be advanced percutaneously intoeither the left or right renal artery via a minimally invasiveintravascular path. However, minimally invasive renal arterial accessmay be challenging, for example, because as compared to some otherarteries that are routinely accessed using catheters, the renal arteriesare often extremely tortuous, may be of relatively small diameter,and/or may be of relatively short length. Furthermore, renal arterialatherosclerosis is common in many patients, particularly those withcardiovascular disease. Renal arterial anatomy also may varysignificantly from patient to patient, which further complicatesminimally invasive access. Significant inter-patient variation may beseen, for example, in relative tortuosity, diameter, length, and/oratherosclerotic plaque burden, as well as in the take-off angle at whicha renal artery branches from the aorta. Apparatus, systems and methodsfor achieving renal neuromodulation via intravascular access shouldaccount for these and other aspects of renal arterial anatomy and itsvariation across the patient population when minimally invasivelyaccessing a renal artery.

In addition to complicating renal arterial access, specifics of therenal anatomy also complicate establishment of stable contact betweenneuromodulatory apparatus and a luminal surface or wall of a renalartery. When the neuromodulatory apparatus includes an energy deliveryelement, such as an electrode, consistent positioning and appropriatecontact force applied by the energy delivery element to the vessel wallare important for predictability. However, navigation is impeded by thetight space within a renal artery, as well as tortuosity of the artery.Furthermore, establishing consistent contact is complicated by patientmovement, respiration, and/or the cardiac cycle because these factorsmay cause significant movement of the renal artery relative to theaorta, and the cardiac cycle may transiently distend the renal artery(i.e., cause the wall of the artery to pulse).

Even after accessing a renal artery and facilitating stable contactbetween neuromodulatory apparatus and a luminal surface of the artery,nerves in and around the adventia of the artery should be safelymodulated via the neuromodulatory apparatus. Effectively applyingthermal treatment from within a renal artery is non-trivial given thepotential clinical complications associated with such treatment. Forexample, the intima and media of the renal artery are highly vulnerableto thermal injury. As discussed in greater detail below, theintima-media thickness separating the vessel lumen from its adventitiameans that target renal nerves may be multiple millimeters distant fromthe luminal surface of the artery. Sufficient energy should be deliveredto or heat removed from the target renal nerves to modulate the targetrenal nerves without excessively cooling or heating the vessel wall tothe extent that the wall is frozen, desiccated, or otherwise potentiallyaffected to an undesirable extent. A potential clinical complicationassociated with excessive heating is thrombus formation from coagulatingblood flowing through the artery. Given that this thrombus may cause akidney infarct, thereby causing irreversible damage to the kidney,thermal treatment from within the renal artery should be appliedcarefully. Accordingly, the complex fluid mechanics and thermodynamicconditions present in the renal artery during treatment, particularlythose that may impact heat transfer dynamics at the treatment site, maybe important in applying energy (e.g., heating thermal energy) and/orremoving heat from the tissue (e.g., cooling thermal conditions) fromwithin the renal artery.

The neuromodulatory apparatus should also be configured to allow foradjustable positioning and repositioning of the energy delivery elementwithin the renal artery since location of treatment may also impactclinical efficacy. For example, it may be tempting to apply a fullcircumferential treatment from within the renal artery given that therenal nerves may be spaced circumferentially around a renal artery. Insome situations, full-circle lesion likely resulting from a continuouscircumferential treatment may be potentially related to renal arterystenosis. Therefore, the formation of more complex lesions along alongitudinal dimension of the renal artery via the mesh structuresdescribed herein and/or repositioning of the neuromodulatory apparatusto multiple treatment locations may be desirable. It should be noted,however, that a benefit of creating a circumferential ablation mayoutweigh the potential of renal artery stenosis or the risk may bemitigated with certain embodiments or in certain patients and creating acircumferential ablation could be a goal. Additionally, variablepositioning and repositioning of the neuromodulatory apparatus may proveto be useful in circumstances where the renal artery is particularlytortuous or where there are proximal branch vessels off the renal arterymain vessel, making treatment in certain locations challenging.Manipulation of a device in a renal artery should also considermechanical injury imposed by the device on the renal artery. Motion of adevice in an artery, for example by inserting, manipulating, negotiatingbends and so forth, may contribute to dissection, perforation, denudingintima, or disrupting the interior elastic lamina.

Blood flow through a renal artery may be temporarily occluded for ashort time with minimal or no complications. However, occlusion for asignificant amount of time should be avoided because to prevent injuryto the kidney such as ischemia. It could be beneficial to avoidocclusion all together or, if occlusion is beneficial to the embodiment,to limit the duration of occlusion, for example to 2-5 minutes.

Based on the above described challenges of (1) renal arteryintervention, (2) consistent and stable placement of the treatmentelement against the vessel wall, (3) effective application of treatmentacross the vessel wall, (4) positioning and potentially repositioningthe treatment apparatus to allow for multiple treatment locations, and(5) avoiding or limiting duration of blood flow occlusion, variousindependent and dependent properties of the renal vasculature that maybe of interest include, for example, (a) vessel diameter, vessel length,intima-media thickness, coefficient of friction, and tortuosity; (b)distensibility, stiffness and modulus of elasticity of the vessel wall;(c) peak systolic, end-diastolic blood flow velocity, as well as themean systolic-diastolic peak blood flow velocity, and mean/maxvolumetric blood flow rate; (d) specific heat capacity of blood and/orof the vessel wall, thermal conductivity of blood and/or of the vesselwall, and/or thermal convectivity of blood flow past a vessel walltreatment site and/or radiative heat transfer; (e) renal artery motionrelative to the aorta induced by respiration, patient movement, and/orblood flow pulsatility: and (f) as well as the take-off angle of a renalartery relative to the aorta. These properties will be discussed ingreater detail with respect to the renal arteries. However, dependent onthe apparatus, systems and methods utilized to achieve renalneuromodulation, such properties of the renal arteries, also may guideand/or constrain design characteristics.

As noted above, an apparatus positioned within a renal artery shouldconform to the geometry of the artery. Renal artery vessel diameter,D_(RA), typically is in a range of about 2-10 mm, with most of thepatient population having a D_(RA) of about 4 mm to about 8 mm and anaverage of about 6 mm. Renal artery vessel length, L_(RA), between itsostium at the aorta/renal artery juncture and its distal branchings,generally is in a range of about 5-70 mm, and a significant portion ofthe patient population is in a range of about 20-50 mm. Since the targetrenal plexus is embedded within the adventitia of the renal artery, thecomposite Intima-Media Thickness, IMT, (i.e., the radial outwarddistance from the artery's luminal surface to the adventitia containingtarget neural structures) also is notable and generally is in a range ofabout 0.5-2.5 mm, with an average of about 1.5 mm. Although a certaindepth of treatment is important to reach the target neural fibers, thetreatment should not be too deep (e.g., >5 mm from inner wall of therenal artery) to avoid non-target tissue and anatomical structures suchas the renal vein.

An additional property of the renal artery that may be of interest isthe degree of renal motion relative to the aorta, induced by respirationand/or blood flow pulsatility. A patient's kidney, which located at thedistal end of the renal artery, may move as much as 4″ cranially withrespiratory excursion. This may impart significant motion to the renalartery connecting the aorta and the kidney, thereby requiring from theneuromodulatory apparatus a unique balance of stiffness and flexibilityto maintain contact between the thermal treatment element and the vesselwall during cycles of respiration. Furthermore, the take-off anglebetween the renal artery and the aorta may vary significantly betweenpatients, and also may vary dynamically within a patient, e.g., due tokidney motion. The take-off angle generally may be in a range of about30°−135°.

V. Conclusion

The above detailed descriptions of embodiments of the technology are notintended to be exhaustive or to limit the technology to the precise formdisclosed above. Although specific embodiments of, and examples for, thetechnology are described above for illustrative purposes, variousequivalent modifications are possible within the scope of thetechnology, as those skilled in the relevant art will recognize. Forexample, while steps are presented in a given order, alternativeembodiments may perform steps in a different order. The variousembodiments described herein may also be combined to provide furtherembodiments.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but well-known structures and functions have not been shown or describedin detail to avoid unnecessarily obscuring the description of theembodiments of the technology. Where the context permits, singular orplural terms may also include the plural or singular term, respectively.For example, as noted previously, although much of the disclosure hereindescribes an energy delivery element 24 (e.g., an electrode) in thesingular, it should be understood that this disclosure does not excludetwo or more energy delivery elements or electrodes.

Moreover, unless the word “or” is expressly limited to mean only asingle item exclusive from the other items in reference to a list of twoor more items, then the use of “or” in such a list is to be interpretedas including (a) any single item in the list, (b) all of the items inthe list, or (c) any combination of the items in the list. Additionally,the term “comprising” is used throughout to mean including at least therecited feature(s) such that any greater number of the same featureand/or additional types of other features are not precluded. It willalso be appreciated that specific embodiments have been described hereinfor purposes of illustration, but that various modifications may be madewithout deviating from the technology. Further, while advantagesassociated with certain embodiments of the technology have beendescribed in the context of those embodiments, other embodiments mayalso exhibit such advantages, and not all embodiments need necessarilyexhibit such advantages to fall within the scope of the technology.Accordingly, the disclosure and associated technology can encompassother embodiments not expressly shown or described herein.

We claim:
 1. A method for neuromodulation treatment of a human patient,the method comprising: delivering energy over a first period of time,via an electrode positioned at a treatment site within a blood vessel ofthe patient, to target neural fibers adjacent a wall of the bloodvessel; maintaining energy delivery at a first predetermined power levelfor a second period of time; increasing energy delivery to a secondpredetermined power level if a temperature value sensed in or near theelectrode is less than a preset threshold temperature following thesecond period of time; obtaining a set of treatment data correspondingto a completed neuromodulation treatment; evaluating the set oftreatment data in view of one or more criteria to determine if avaluation of the completed neuromodulation treatment is within apre-determined range; and providing an indication as to whether thevaluation of the completed neuromodulation treatment is within thepre-determined range.
 2. The method of claim 1 wherein delivering energyover a first period of time, via the electrode, to target neural fiberscomprises increasing energy delivery at a generally constant rate to thefirst predetermined first power level over the first period of time. 3.The method of claim 1 wherein obtaining the set of treatment datacomprises obtaining a first set of treatment data corresponding to afirst completed neuromodulation treatment, and wherein the methodfurther comprises: modifying the first predetermined power level, thefirst period of time, the second period of time, and/or the secondpredetermined power level based, at least in part, on the evaluation ofthe first treatment data and the indication as to whether the valuationof the first completed neuromodulation treatment is within thepre-determined range; performing a second neuromodulation treatmentusing the modified first predetermined power level, modified firstperiod of time, modified second period of time, and/or modified secondpredetermined power level; and obtaining a second set of treatment datacorresponding to a second completed neuromodulation treatment.
 4. Themethod of claim 1 wherein providing an indication comprises displaying amessage on a display screen of an energy generator used to administerthe neuromodulation treatment.
 5. The method of claim 4 whereinproviding an indication as to whether the completed neuromodulationtreatment was within the pre-determined range comprises: displaying afirst message on the display screen if the valuation of theneuromodulation treatment is within the pre-determined range; anddisplaying a second, different message on the display screen if thevaluation of the neuromodulation treatment indicated that treatment didnot proceed as expected.
 6. The method of claim 1 wherein the presetthreshold temperature is from about 45 degrees Celsius to about 90degrees Celsius.
 7. The method of claim 1 wherein the preset thresholdtemperature is from about 60 degrees Celsius to about 75 degreesCelsius.
 8. The method of claim 1 wherein the preset thresholdtemperature is about 65 degrees Celsius.
 9. The method of claim 1wherein the first predetermined power level is about 5 watts.
 10. Themethod of claim 1 wherein the first period of time is about 15 seconds.11. The method of claim 1 wherein the second period of time is at least3 seconds.
 12. The method of claim 1 the second predetermined powerlevel is about 6 watts.
 13. The method of claim 1 wherein the secondpredetermined power level is about 8 watts.
 14. The method of claim 1wherein the blood vessel comprises a renal artery of the patient. 15.The method of claim 1 wherein obtaining a set of treatment datacorresponding to a completed treatment comprises obtaining the treatmentdata, at least in part, via the electrode.
 16. The method of claim 1wherein obtaining a set of treatment data comprises measuring one ormore of the following: temperature in or near the electrode, time,electrode impedance, power delivered to the electrode, blood flow in theblood vessel, blood flow velocity in the blood vessel, volumetric bloodflow rate in the blood vessel, blood pressure, or heart rate of thepatient.
 17. The method of claim 1 wherein obtaining a set of treatmentdata comprises taking measurements related to one or more of thefollowing: a change in temperature in or near the electrode over aspecified time, a maximum temperature in or near the electrode, amaximum average temperature in or near the electrode, a minimumtemperature in or near the electrode, a temperature in or near theelectrode at a predetermined or calculated time relative to apredetermined or calculated temperature, an average temperature in ornear the electrode over a specified time, a maximum blood flow in theblood vessel, a minimum blood flow in the blood vessel, a blood flow inthe blood vessel at a predetermined or calculated time relative to apredetermined or calculated blood flow, an average blood flow in theblood vessel over time, a maximum electrode impedance, a minimumelectrode impedance, an electrode impedance at a predetermined orcalculated time relative to a predetermined or calculated impedance, achange in electrode impedance over a specified time, or a change inelectrode impedance relative to a change in temperature in or near theelectrode over a specified time.
 18. The method of claim 1 whereinevaluating the set of treatment data comprises performing a lineardiscriminant analysis to generate a score and using the score todetermine whether the completed neuromodulation treatment was within thepre-determined range or if the completed treatment did not proceed asexpected.
 19. A method for renal neuromodulation treatment of a humanpatient via an electrode positioned within a renal artery of thepatient, the method comprising: delivering radio frequency (RF) energy,via the electrode, to target renal nerves proximate the renal artery,wherein delivering RF energy comprises— increasing energy delivery tothe electrode a predetermined first power level over a first period oftime; maintaining energy delivery at the predetermined first power levelfor a second period of time; and increasing energy delivery to apredetermined second power level if the temperature value measured in ornear the electrode is less than a preset threshold temperature followingthe second period of time, wherein the increase in energy deliveryfollowing the second period of time continues until the power level hasreached a target maximum power threshold; and evaluating the renalneuromodulation treatment of the patient, wherein the evaluationcomprises— obtaining a set of treatment data corresponding to acompleted renal neuromodulation treatment; evaluating the set oftreatment data in view of one or more criteria to determine if avaluation of the completed renal neuromodulation treatment is within apre-determined range; and providing an indication as to whether thevaluation of the completed renal neuromodulation treatment is within thepre-determined range.
 20. The method of claim 19 wherein delivering RFenergy, via the electrode, to target renal nerves comprises at leastpartially ablating the target renal nerves.
 21. The method of claim 19wherein: evaluating the set of treatment data comprises generating ascore used to determine whether the completed renal neuromodulationtreatment was within the pre-determined range or if the completed renalneuromodulation treatment did not proceed as expected; providing anindication as to whether the completed renal neuromodulation treatmentwas within the pre-determined range comprises (a) displaying a firstmessage on a display screen if the valuation of the renalneuromodulation treatment is within the pre-determined range, and (b)displaying a second, different message on the display screen if thevaluation of the renal neuromodulation treatment indicated thattreatment did not proceed as expected.